Translational research in traumatic brain injury

Research in our laboratory and collaborative group is focused on the development of novel therapeutic and diagnostic strategies for traumatic brain injury (TBI). TBI is a major cause of morbidity and mortality worldwide, a major risk factor for the development of Alzheimer’s Disease, and the single leading cause of permanent disability in people under age 45 in the United States. Supportive care is the only effective treatment at present.

Our work has focused on the role of the amyloid-beta peptide (Abeta) in TBI. Deposition of the Abeta peptide, one of the pathological hallmarks of Alzheimer’s disease, also occurs in a significant number of young TBI patients. Previous research demonstrates that the levels of Abeta change dramatically after TBI and that injury to axons may play an important role in Abeta deposition. Our preliminary results suggest that therapeutics that block the effects of Abeta may improve cognitive outcomes in a transgenic mouse model of TBI. This work may lead to improved therapeutic options for patients with TBI in the future.

Recently, we have begun to measure Abeta levels following TBI and other brain injuries in both mice and human patients using intracerebral microdialysis. A major aim is to use microdialysis to measure the effects of therapeutics that target Abeta, and more generally to perform pharmacokinetic and pharmacodynamic studies in the human brain.

A second major line of research has been in the role of Apolipoprotein E (ApoE) in TBI. The APOE4 allele is the strongest genetic risk factor for both poor outcome after TBI and the development of Alzheimer’s disease. We are using gene-targeted and transgenic mice to investigate the role of ApoE in TBI. ApoE interactions with Abeta after TBI and effects on axonal injury are of particular interest. The ultimate goal is the development of ApoE-based therapeutics.

An area in which great progress has been made recently is in the detection of traumatic axonal injury using a new MRI technique called Diffusion Tensor Imaging (DTI). We are validating this method in a mouse model of TBI using direct, quantitative comparison of DTI signal abnormalities to histological and electron microscopic “gold-standards.” DTI appears to be considerably more sensitive to white matter injury than conventional imaging methods. Future work will include the use of DTI and other advanced MRI methods in human TBI patients, with the goals of improving our ability to detect clinically significant axonal injury after relatively minor head injuries, assist with prognosis, and guide stratification of patients for therapeutic trials.